Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome
Elena Gallo MacFarlane, … , Jennifer P. Habashi, Harry C. Dietz
Elena Gallo MacFarlane, … , Jennifer P. Habashi, Harry C. Dietz
Published February 5, 2019; First published January 7, 2019
Citation Information: J Clin Invest. 2019;129(2):659-675. https://doi.org/10.1172/JCI123547.
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Categories: Research Article Vascular biology

Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

Abstract

The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field–derived (SHF-derived), but not neighboring cardiac neural crest–derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands. The preserved TGF-β signaling potential in CNC-derived VSMCs associated, in vivo, with increased Smad2/3 phosphorylation. CNC-, but not SHF-specific, deletion of Smad2 preserved aortic wall architecture and reduced aortic dilation in this mouse model of LDS. Taken together, these data suggest that aortic root aneurysm predisposition in this LDS mouse model depends both on defective Smad signaling in SHF-derived VSMCs and excessive Smad signaling in CNC-derived VSMCs. This work highlights the importance of considering the regional microenvironment and specifically lineage-dependent variation in the vulnerability to mutations in the development and testing of pathogenic models for aortic aneurysm.

Authors

Elena Gallo MacFarlane, Sarah J. Parker, Joseph Y. Shin, Benjamin E. Kang, Shira G. Ziegler, Tyler J. Creamer, Rustam Bagirzadeh, Djahida Bedja, Yichun Chen, Juan F. Calderon, Katherine Weissler, Pamela A. Frischmeyer-Guerrerio, Mark E. Lindsay, Jennifer P. Habashi, Harry C. Dietz

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Figure 8

Smad2 deletion in CNC- but not SHF-derived cells ameliorates aortic pathology in Tbr1MR/+ mice.

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Smad2 deletion in CNC- but not SHF-derived cells ameliorates aortic pat...
Absolute size and aortic root growth rate in 20-week-old control (Tbr1+/+) and mutant (Tbr1MR/+) mice in which Smad2 (abbreviated Sm2) is not deleted (Sm2Ctrl), deleted in SHF-derived cells (Sm2SHF) (A) or deleted in CNC-derived cells (Sm2CNC) (B) (for all groups n ≥ 8). P values refer to Kruskal-Wallis test with FDR-based multiple comparison correction. (C) Representative images of Masson’s trichrome staining of the aortic root of mice of the indicated genotype at 20 weeks of age. Scale bars: 500 μm. Experiment was conducted at least 3 times. (D) Representative images of Masson’s trichrome staining of the aortic root of mice of the indicated genotype at 20 weeks of age. Scale bars: 100 μm. Image enhancement for visual display was applied uniformly to all panels. Experiment was conducted at least 3 times. Numerical data are presented as scatter dot-plots with boxes, with the box denoting the mean; error bars identify the 95% confidence interval.